POS0633 SAFETY OF GENETICALLY PROXIED TNF INHIBITION ON PREGNANCY RELATED OUTCOMES
Authors: S. S. Zhao, D. Gill
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> TNF inhibitors (TNFi) have greatly improved the management of rheumatoid arthritis and several immune mediated inflammatory diseases. Although these diseases commonly start during childbearing age, the safety of TNFi in pregnancy is unclear, and is unlikely to change as clinical trials continue to exclude pregnant women for concern of harm to the foetus. Lack of scientific evidence to inform treatment decisions can contribute to maternal anxiety and suboptimally controlled disease. Naturally occurring variations in the genes that encode the protein drug target can provide population-level insights into safety, without exposing pregnant women to these drugs. <h3>Objectives</h3> To investigate the association between genetically proxied TNFi and pregnancy related outcomes, namely, spontaneous abortion, preterm birth, pre-eclampsia or eclampsia, gestational hypertension, gestational diabetes mellitus, and birthweight of the firstborn child. <h3>Methods</h3> To proxy TNFi, we selected uncorrelated (r<sup>2</sup>&gt;0.1) genome-wide significant (p&lt;5x10<sup>-8</sup>) single nucleotide polymorphisms within the gene encoding TNF receptor 1 (<i>TNFRSF1A</i>, build GRCh37/hg19: chromosome 12:6437923-6451280) from a genome wide association study (GWAS) of CRP among 337,199 individuals. CRP was (inverse rank-normal) transformed, with estimates scaled to per standard deviation (SD=4.35 mg/L) change in CRP. We selected CRP as the biomarker because clinical data show its suppression with TNFi. We estimated the F statistics of the instrument (square of the beta divided by square of the standard error) with F &gt;10 being suggestive of adequate instrument strength. Genetic association data for spontaneous abortion (15,073 cases 135,962 female controls), preterm birth (7,678 cases 14,8153 controls), pre-eclampsia or eclampsia (6,436 cases 176,113 controls), gestational hypertension (7,503 cases 176,113 controls) and gestational diabetes (7,676 cases 130,424 controls) were derived from the FinnGen study. Data for firstborn birth weight (grouped into &lt;7, 7 or &gt;7 pounds (~3.2kg)) was obtained from 200,272 women in the UK Biobank. We included a positive control outcome, ankylosing spondylitis, and a negative control, multiple sclerosis. We used ratio method and, where an association was found, applied colocalization to test for genetic confounding. <h3>Results</h3> We identified one variant, rs1800693, to instrument TNFi. The F statistic was 65 suggesting adequate instrument strength. We found no evidence of associations between genetically proxied TNFi and any pregnancy related outcome (Figure 1) except gestational diabetes (OR 0.12 per SD reduction in CRP; 95%CI 0.03 to 0.57; p=0.007). The posterior probability of colocalization between CRP and gestational diabetes in the <i>TNFRSF1A</i> gene region was 99% conditional on the presence of a causal variant for the outcome, which provide evidence against genetic confounding. <h3>Conclusion</h3> We found no genetic evidence to suggest that TNFi is harmful for the selected outcomes relating to pregnancy. These results are reassuring and concur with observational data where women were exposed to TNFi during pregnancy. There was evidence that TNFi may be associated with lower risk of gestational diabetes. Further studies are needed to examine whether this is specific to diabetes during pregnancy or more generally. It is important to note that subtle differences in CRP levels through genetic variation may not be comparable to effects of pharmacological inhibition, and life-long exposure studied herein may differ from shorter duration of pharmacological intervention. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Sizheng Steven Zhao: None declared, Dipender Gill Employee of: Employed part-time by Novo Nordisk outside of submitted work.